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Year of Publication
1.  Brain and Behavior 
Brain and Behavior  2014;4(2):i-iii.
doi:10.1002/brb3.165
PMCID: PMC3967527
3.  N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities 
Brain and Behavior  2014;4(2):108-122.
Background
There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.
Aim and discussion
Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht–Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.
Conclusion
Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.
doi:10.1002/brb3.208
PMCID: PMC3967529
N-acetylcysteine; neurological disorder; treatment
4.  Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection 
Brain and Behavior  2013;4(2):123-142.
Background
The purpose of this study was to characterize hepatitis C virus (HCV)-associated differences in the expression of 47 inflammatory factors and to evaluate the potential role of peripheral immune activation in HCV-associated neuropsychiatric symptoms—depression, anxiety, fatigue, and pain. An additional objective was to evaluate the role of immune factor dysregulation in the expression of specific neuropsychiatric symptoms to identify biomarkers that may be relevant to the treatment of these neuropsychiatric symptoms in adults with or without HCV.
Methods
Blood samples and neuropsychiatric symptom severity scales were collected from HCV-infected adults (HCV+, n = 39) and demographically similar noninfected controls (HCV−, n = 40). Multi-analyte profile analysis was used to evaluate plasma biomarkers.
Results
Compared with HCV− controls, HCV+ adults reported significantly (P < 0.050) greater depression, anxiety, fatigue, and pain, and they were more likely to present with an increased inflammatory profile as indicated by significantly higher plasma levels of 40% (19/47) of the factors assessed (21%, after correcting for multiple comparisons). Within the HCV+ group, but not within the HCV− group, an increased inflammatory profile (indicated by the number of immune factors > the LDC) significantly correlated with depression, anxiety, and pain. Within the total sample, neuropsychiatric symptom severity was significantly predicted by protein signatures consisting of 4–10 plasma immune factors; protein signatures significantly accounted for 19–40% of the variance in depression, anxiety, fatigue, and pain.
Conclusions
Overall, the results demonstrate that altered expression of a network of plasma immune factors contributes to neuropsychiatric symptom severity. These findings offer new biomarkers to potentially facilitate pharmacotherapeutic development and to increase our understanding of the molecular pathways associated with neuropsychiatric symptoms in adults with or without HCV.
doi:10.1002/brb3.200
PMCID: PMC3967530
Anxiety; biological markers; chronic infection; cytokines; depression; fatigue; pain
5.  Unilateral disruptions in the default network with aging in native space 
Brain and Behavior  2013;4(2):143-157.
Background
Disruption of the default-mode network (DMN) in healthy elders has been reported in many studies.
Methods
In a group of 51 participants (25 young, 26 elder) we examined DMN connectivity in subjects' native space. In the native space method, subject-specific regional masks (obtained independently for each subject) are used to extract regional fMRI times series. This approach substitutes the spatial normalization and subsequent smoothing used in prevailing methods, affords more accurate spatial localization, and provides the power to examine connectivity separately in the two hemispheres instead of averaging regions across hemispheres.
Results
The native space method yielded new findings which were not detectable by the prevailing methods. The most reliable and robust disruption in elders' DMN connectivity were found between supramarginal gyrus and superior-frontal cortex in the right hemisphere only. The mean correlation between these two regions in young participants was about 0.5, and dropped significantly to 0.04 in elders (P = 2.1 × 10−5). In addition, the magnitude of functional connectivity between these regions in the right hemisphere correlated with memory (P = 0.05) and general fluid ability (P = 0.01) in elder participants and with speed of processing in young participants (P = 0.008). These relationships were not observed in the left hemisphere.
Conclusion
These findings suggest that analysis of DMN connectivity in subjects' native space can improve localization and power and that it is important to examine connectivity separately in each hemisphere.
doi:10.1002/brb3.202
PMCID: PMC3967531
Age-related brain change; cognitive performance; fMRI analysis; interhemispheric averaging; resting-state BOLD fMRI; spatial normalization; SPM
6.  White matter integrity is associated with alcohol cue reactivity in heavy drinkers 
Brain and Behavior  2013;4(2):158-170.
Neuroimaging studies have shown that white matter damage accompanies excessive alcohol use, but the functional correlates of alcohol-related white matter disruption remain unknown. This study applied tract-based spatial statistics (TBSS) to diffusion tensor imaging (DTI) data from 332 heavy drinkers (mean age = 31.2 ± 9.4; 31% female) to obtain averaged fractional anisotropy (FA) values of 18 white matter tracts. Statistical analyses examined correlations of FA values with blood-oxygenation-level-dependent (BOLD) response to an alcohol taste cue, measured with functional magnetic resonance imaging (fMRI). FA values of nine white matter tracts (anterior corona radiata, body of corpus callosum, cingulate gyrus, external capsule, fornix, inferior frontooccipital fasciculus, posterior corona radiata, retrolenticular limb of internal capsule, and superior longitudinal fasciculus) were significantly, negatively correlated with BOLD activation in medial frontal gyrus, parahippocampal gyrus, fusiform gyrus, cingulum, thalamus, caudate, putamen, insula, and cerebellum. The inverse relation between white matter integrity and functional activation during the alcohol taste cue provides support for the hypothesis that lower white matter integrity in frontoparietal and corticolimbic networks is a factor in loss of control over alcohol consumption.
doi:10.1002/brb3.204
PMCID: PMC3967532
Alcohol use disorders; diffusion tensor imaging; functional magnetic resonance imaging; tract-based spatial statistics; white matter
7.  Brain training: rationale, methods, and pilot data for a specific visuomotor/visuospatial activity program to change progressive cognitive decline 
Brain and Behavior  2013;4(2):171-179.
Introduction
Research in the field of the aging brain has evolved to the extent that it is now commonly understood that actively engaging in cognitive tasks provides the potential of being beneficial in affecting the trajectory of age-related cognitive decline. What remains to be examined is the extent, and type, of program required to effect change in aging cognitively impaired individuals.
Methods
To address this issue, a cognitive program focusing on the use of visuospatial (VS)/visuomotor (VM) elements was applied to a group of six older individuals with identified progressive cognitive impairments. It was hypothesized that using tasks with VS and VM components may be beneficial in supporting overall brain performance, and subsequently assist individuals to perform well in various cognitive and behavioral tasks.
Results
Results showed that on many evaluative measures individuals remained stable, or improved in performance with medium-to-large effect sizes (e.g., 0.3–1.0). Thus, in a cognitively impaired population sample where decline would be the norm, our participants improved or remained stable.
Conclusion
The novel application of a VS/VM training program shows promise in addressing global cognitive decline, by targeting a brain area susceptible to early disruptions and providing it with additional and ongoing stimulative tasks in an effort to bolster its functioning and subsequently overall brain functioning.
doi:10.1002/brb3.196
PMCID: PMC3967533
Cognitive impairment; cognitive training; visuospatial/visuomotor
8.  Neural differences in processing of case particles in Japanese: an fMRI study 
Brain and Behavior  2013;4(2):180-186.
Introduction
In subject–object–verb (SOV) languages, such as Japanese, sentence processing proceeds incrementally to the late presentation of the head (verb). Japanese case particles play a crucial role in sentence processing; however, little is known about how these particles are processed. In particular, it is still unclear how the functional difference between case particles is represented in the human brain.
Methods
In this study, we conducted an fMRI experiment using an event-related design to directly compare brain activity during Japanese case particle processing among the nominative case ga, accusative case o, and dative case ni. Twenty five native Japanese speakers were asked to judge whether the presented character was a particle in a particle judgment task and whether the character ended with a specific vowel in a phonological judgment task, which was used as a control condition.
Results
A particle comparison demonstrated that the processing of ni was associated with significantly weaker brain activity than that of ga and o in the left middle frontal gyrus (MFG) and the inferior frontal gyrus (IFG). Significantly greater brain activity associated with ni relative to ga in the right IFG was also observed.
Conclusion
These results suggest that the Japanese case particles ga, ni, and o are represented differently in the brain.
doi:10.1002/brb3.201
PMCID: PMC3967534
Comprehension; functional MRI; language; neuroimaging; syntax
9.  Fgf2 improves functional recovery—decreasing gliosis and increasing radial glia and neural progenitor cells after spinal cord injury 
Brain and Behavior  2014;4(2):187-200.
Objectives
A major impediment for recovery after mammalian spinal cord injury (SCI) is the glial scar formed by proliferating reactive astrocytes. Finding factors that may reduce glial scarring, increase neuronal survival, and promote neurite outgrowth are of major importance for improving the outcome after SCI. Exogenous fibroblast growth factor (Fgf) has been shown to decrease injury volume and improve functional outcome; however, the mechanisms by which this is mediated are still largely unknown.
Methods
In this study, Fgf2 was administered for 2 weeks in mice subcutaneously, starting 30 min after spinal cord hemisection.
Results
Fgf2 treatment decreased the expression of TNF-a at the lesion site, decreased monocyte/macrophage infiltration, and decreased gliosis. Fgf2 induced astrocytes to adopt a polarized morphology and increased expression of radial markers such as Pax6 and nestin. In addition, the levels of chondroitin sulfate proteoglycans (CSPGs), expressed by glia, were markedly decreased. Furthermore, Fgf2 treatment promotes the formation of parallel glial processes, “bridges,” at the lesion site that enable regenerating axons through the injury site. Additionally, Fgf2 treatment increased Sox2-expressing cells in the gray matter and neurogenesis around and at the lesion site. Importantly, these effects were correlated with enhanced functional recovery of the left paretic hind limb.
Conclusions
Thus, early pharmacological intervention with Fgf2 following SCI is neuroprotective and creates a proregenerative environment by the modulation of the glia response.
doi:10.1002/brb3.172
PMCID: PMC3967535
Astroglia; GFAP; nestin; Pax6; progenitors; regeneration; Sox2; spinal cord injury
10.  Neural substrates of socioemotional self-awareness in neurodegenerative disease 
Brain and Behavior  2014;4(2):201-214.
Background
Neuroimaging studies examining neural substrates of impaired self-awareness in patients with neurodegenerative diseases have shown divergent results depending on the modality (cognitive, emotional, behavioral) of awareness. Evidence is accumulating to suggest that self-awareness arises from a combination of modality-specific and large-scale supramodal neural networks.
Methods
We investigated the structural substrates of patients' tendency to overestimate or underestimate their own capacity to demonstrate empathic concern for others. Subjects' level of empathic concern was measured using the Interpersonal Reactivity Index, and subject-informant discrepancy scores were used to predict regional atrophy pattern, using voxel-based morphometry analysis. Of the 102 subjects, 83 were patients with neurodegenerative diseases such as behavioral variant frontotemporal dementia (bvFTD) or semantic variant primary progressive aphasia (svPPA); the other 19 were healthy older adults.
Results
bvFTD and svPPA patients typically overestimated their level of empathic concern compared to controls, and overestimating one's empathic concern predicted damage to predominantly right-hemispheric anterior infero-lateral temporal regions, whereas underestimating one's empathic concern showed no neuroanatomical basis.
Conclusions
These findings suggest that overestimation and underestimation of one's capacity for empathic concern cannot be interpreted as varying degrees of the same phenomenon, but may arise from different pathophysiological processes. Damage to anterior infero-lateral temporal regions has been associated with semantic self-knowledge, emotion processing, and social perspective taking; neuropsychological functions partly associated with empathic concern itself. These findings support the hypothesis that—at least in the socioemotional domain—neural substrates of self-awareness are partly modality-specific.
doi:10.1002/brb3.211
PMCID: PMC3967536
Affective perspective taking; dementia; empathy; infero-lateral temporal cortex; neurodegeneration; semantic self-knowledge; unawareness; voxel-based morphometry
11.  A Neuregulin-1 schizophrenia susceptibility variant causes perihippocampal fiber tract anomalies in healthy young subjects 
Brain and Behavior  2014;4(2):215-226.
Background: Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis. Methods: We compared fractional anisotropy in 54 subjects that were either homozygous for the risk C allele carriers (n = 31) for rs35753505 or homozygous for the T allele (n = 23) using diffusion tensor imaging with 3T. Tract-Based Spatial Statistics (TBSS), a method especially developed for diffusion data analysis, was used to improve white matter registration and to focus the statistical analysis to major fiber tracts. Results: Statistical analysis showed that homozygous risk C allele carriers featured elevated fractional anisotropy (FA) in the right perihippocampal region and the white matter proximate to the left area 4p as well as the right hemisphere of the cerebellum. We found three clusters of reduced FA values in homozygous C allele carriers: in the left superior parietal region, the right prefrontal white matter and in the deep white matter of the left frontal lobe. Conclusion: Our results highlight the importance of Neuregulin-1 for structural connectivity of the right medial temporal lobe. This finding is in line with well known neuropathological findings in this region in patients with schizophrenia.
doi:10.1002/brb3.203
PMCID: PMC3967537
Anatomic connectivity; brain; DTI; gene; hippocampus; MRI; Neuregulin-1
12.  Functional MRI mapping of visual function and selective attention for performance assessment and presurgical planning using conjunctive visual search 
Brain and Behavior  2014;4(2):227-237.
Background
Accurate mapping of visual function and selective attention using fMRI is important in the study of human performance as well as in presurgical treatment planning of lesions in or near visual centers of the brain. Conjunctive visual search (CVS) is a useful tool for mapping visual function during fMRI because of its greater activation extent compared with high-capacity parallel search processes.
Aims
The purpose of this work was to develop and evaluate a CVS that was capable of generating consistent activation in the basic and higher level visual areas of the brain by using a high number of distractors as well as an optimized contrast condition.
Materials and methods
Images from 10 healthy volunteers were analyzed and brain regions of greatest activation and deactivation were determined using a nonbiased decomposition of the results at the hemisphere, lobe, and gyrus levels. The results were quantified in terms of activation and deactivation extent and mean z-statistic.
Results
The proposed CVS was found to generate robust activation of the occipital lobe, as well as regions in the middle frontal gyrus associated with coordinating eye movements and in regions of the insula associated with task-level control and focal attention. As expected, the task demonstrated deactivation patterns commonly implicated in the default-mode network. Further deactivation was noted in the posterior region of the cerebellum, most likely associated with the formation of optimal search strategy.
Conclusion
We believe the task will be useful in studies of visual and selective attention in the neuroscience community as well as in mapping visual function in clinical fMRI.
doi:10.1002/brb3.213
PMCID: PMC3967538
fMRI; magnetic resonance imaging; neurosurgery; occipital lobe; visual function
13.  Enhanced cardiac perception predicts impaired performance in the Iowa Gambling Task in patients with panic disorder 
Brain and Behavior  2014;4(2):238-246.
Objective
Somatic marker theory predicts that somatic cues serve intuitive decision making; however, cardiovascular symptoms are threat cues for patients with panic disorder (PD). Therefore, enhanced cardiac perception may aid intuitive decision making only in healthy individuals, but impair intuitive decision making in PD patients.
Methods
PD patients and age-and sex-matched volunteers without a psychiatric diagnosis (n = 17, respectively) completed the Iowa Gambling Task (IGT) as a measure of intuitive decision making. Interindividual differences in cardiac perception were assessed with a common mental-tracking task.
Results
In line with our hypothesis, we found a pattern of opposing associations (Fisher's Z = 1.78, P = 0.04) of high cardiac perception with improved IGT-performance in matched control-participants (r = 0.36, n = 14) but impaired IGT-performance in PD patients (r = −0.38, n = 13).
Conclusion
Interoceptive skills, typically assumed to aid intuitive decision making, can have the opposite effect in PD patients who experience interoceptive cues as threatening, and tend to avoid them. This may explain why PD patients frequently have problems with decision making in everyday life. Screening of cardiac perception may help identifying patients who benefit from specifically tailored interventions.
doi:10.1002/brb3.206
PMCID: PMC3967539
Cardiac perception; decision making; interoception; Iowa Gambling Task; panic disorder; somatic marker hypothesis
14.  The attentional-relevance and temporal dynamics of visual-tactile crossmodal interactions differentially influence early stages of somatosensory processing 
Brain and Behavior  2014;4(2):247-260.
Background
Crossmodal interactions between relevant visual and tactile inputs can enhance attentional modulation at early stages in somatosensory cortices to achieve goal-oriented behaviors. However, the specific contribution of each sensory system during attentional processing remains unclear. We used EEG to investigate the effects of visual priming and attentional relevance in modulating somatosensory cortical responses.
Methods
Healthy adults performed a sensory integration task that required scaled motor responses dependent on the amplitudes of tactile and visual stimuli. Participants completed an attentional paradigm comprised of 5 conditions that presented sequential or concurrent pairs of discrete stimuli with random amplitude variations: 1) tactile-tactile (TT), 2) visual-visual (VV), 3) visual-tactile simultaneous (SIM), 4) tactile-visual delay (TVd), and 5) visual-tactile delay (VTd), each with a 100 ms temporal delay between stimulus onsets. Attention was directed to crossmodal conditions and graded motor responses representing the summation of the 2 stimulus amplitudes were made.
Results
Results of somatosensory ERPs showed that the modality-specific components (P50, P100) were sensitive to i) the temporal dynamics of crossmodal interactions, and ii) the relevance of these sensory signals for behaviour.
Conclusion
Notably, the P50 amplitude was greatest in the VTd condition, suggesting that presentation of relevant visual information for upcoming movement modulates somatosensory processing in modality-specific cortical regions, as early as the primary somatosensory cortex (SI).
doi:10.1002/brb3.210
PMCID: PMC3967540
Attention; crossmodal; ERPs; event-related potentials; sensorimotor integration; somatosensory cortex; tactile; visual
15.  Brain microstructural changes and cognitive correlates in patients with pure obsessive compulsive disorder 
Brain and Behavior  2014;4(2):261-277.
Object
The aim of this study was to investigate macrostructural and microstructural brain changes in patients with pure obsessive compulsive disorder (OCD) and to examine the relationship between brain structure and neuropsychological deficits.
Method
20 patients with OCD underwent a comprehensive neuropsychological battery. A combined voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analysis was used to capture gray matter (GM) and white matter changes in OCD patients as compared to pair-matched healthy volunteers. Multiple regression designs explored the relationship between cognition and neuroimaging parameters.
Results
OCD patients had increased mean diffusivity (MD) in GM nodes of the orbitofronto-striatal loop (left dorsal anterior cingulate [Z = 3.67, P < 0.001] left insula [Z = 3.35 P < 0.001] left thalamus [Z = 3.59, P < 0.001] left parahippocampal gyrus [Z = 3.77 P < 0.001]) and in lateral frontal and posterior associative cortices (right frontal operculum [Z = 3.42 P < 0.001], right temporal lobe [Z = 3.79 P < 0.001] left parietal lobe [Z = 3.91 P < 0.001]). Decreased fractional anisotropy (FA) was detected in intrahemispheric (left superior longitudinal fasciculus [Z = 4.07 P < 0.001]) and interhemispheric (body of corpus callosum [CC, Z = 4.42 P < 0.001]) bundles. Concurrently, the semantic fluency score, a measure of executive control processes, significantly predicted OCD diagnosis (Odds Ratio = 1.37; 95% Confidence Intervals = 1.09–1.73; P = 0.0058), while variation in performance was correlated with increased MD in left temporal (Z = 4.25 P < 0.001) and bilateral parietal regions (left Z = 3.94, right Z = 4.19 P < 0.001), and decreased FA in the right posterior corona radiata (Z = 4.07 P < 0.001) and the left corticospinal tract (Z = 3.95 P < 0.001).
Conclusions
The reported deficit in executive processes and the underlying microstructural alterations may qualify as behavioral and biological markers of OCD.
doi:10.1002/brb3.212
PMCID: PMC3967541
DTI; neuroimaging; neuropsychology; obsessive compulsive disorder; VBM
16.  Pavlovian-conditioned alcohol-seeking behavior in rats is invigorated by the interaction between discrete and contextual alcohol cues: implications for relapse 
Brain and Behavior  2014;4(2):278-289.
Introduction
Drug craving can be independently stimulated by cues that are directly associated with drug intake (discrete drug cues), as well as by environmental contexts in which drug use occurs (contextual drug cues). We tested the hypothesis that the context in which a discrete alcohol-predictive cue is experienced can influence how robustly that cue stimulates alcohol-seeking behavior.
Methods
Male, Long-Evans rats received Pavlovian discrimination training (PDT) sessions in which one conditioned stimulus (CS+; 16 trials/session) was paired with ethanol (0.2 mL/CS+) and a second stimulus (CS−; 16 trials/session) was not. PDT occurred in a specific context, and entries into a fluid port where ethanol was delivered were measured during each CS. Next, rats were acclimated to an alternate (nonalcohol) context where cues and ethanol were withheld. Responses to the nonextinguished CS+ and CS− were then tested without ethanol in the alcohol-associated PDT context, the nonalcohol context or a third, novel context.
Results
Across PDT the CS+ elicited more port entries than the CS−, indicative of Pavlovian discrimination learning. At test, the CS+ elicited more port entries than the CS− in all three contexts: however, alcohol seeking driven by the CS+ was more robust in the alcohol-associated context. In a separate experiment, extinguishing the context-alcohol association did not influence subsequent CS+ responding but reduced alcohol seeking during non-CS+ intervals during a spontaneous recovery test.
Conclusion
These results indicate that alcohol-seeking behavior driven by a discrete Pavlovian alcohol cue is strongly invigorated by an alcohol context, and suggest that contexts may function as excitatory Pavlovian conditioned stimuli that directly trigger alcohol-seeking behavior.
doi:10.1002/brb3.216
PMCID: PMC3967542
Alcoholism; context; ethanol; learning; Pavlovian-conditioning; reinstatement; renewal
17.  BDNF Met66 modulates the cumulative effect of psychosocial childhood adversities on major depression in adolescents 
Brain and Behavior  2014;4(2):290-297.
Background
The interplay among lifetime adversities and the genetic background has been previously examined on a variety of measures of depression; however, only few studies have focused on major depression disorder (MDD) in adolescence.
Methods
Using clinical data and DNA samples from mouthwash gathered from an epidemiological study on the prevalence of mental disorders in youths between 12 and 17 years old, we tested the statistical interaction between a set of psychosocial adversities experienced during childhood (CAs) with two common polymorphisms in the brain-derived neurotrophic factor (BDNF) (Val66Met) and SLC6A4 (L/S) genes on the probability of suffering MDD in adolescence.
Results
Genotype or allele frequencies for both polymorphisms were similar between groups of comparison (MDD N = 246; controls N = 270). The CAs factors: Abuse, neglect, and family dysfunctions; parental maladjustment, parental death, and to have experienced a life-threatening physical illness were predictors of clinical depression in adolescents. Remarkably, the cumulative number of psychosocial adversities was distinctly associated with an increase in the prevalence of depression but only in those Val/Val BDNF individuals; while the possession of at least a copy of the BDNF Met allele (i.e., Met +) was statistically linked with a “refractory” or resilient phenotype to the noticeable influence of CAs.
Conclusion
Liability or resilience to develop MDD in adolescence is dependent of a complex interplay between particular environmental exposures and a set of plasticity genes including BDNF. A better understanding of these factors is important for developing better prevention and early intervention measures.
doi:10.1002/brb3.220
PMCID: PMC3967543
Adolescence; brain-derived neurotrophic factor gene; childhood adversities; major depression; Mexican; serotonin transporter gene
18.  Genome-wide polygenic scoring for a 14-year long-term average depression phenotype 
Brain and Behavior  2014;4(2):298-311.
Background
Despite moderate heritability estimates for depression-related phenotypes, few robust genetic predictors have been identified. Potential explanations for this discrepancy include the use of phenotypic measures taken from a single time point, rather than integrating information over longer time periods via multiple assessments, and the possibility that genetic risk is shaped by multiple loci with small effects.
Methods
We developed a 14-year long-term average depression measure based on 14 years of follow-up in the Nurses' Health Study (NHS; N = 6989 women). We estimated polygenic scores (PS) with internal whole-genome scoring (NHS-GWAS-PS). We also constructed PS by applying two external PS weighting algorithms from independent samples, one previously shown to predict depression (GAIN-MDD-PS) and another from the largest genome-wide analysis currently available (PGC-MDD-PS). We assessed the association of all three PS with our long-term average depression phenotype using linear, logistic, and quantile regressions.
Results
In this study, the three PS approaches explained at most 0.2% of variance in the long-term average phenotype. Quantile regressions indicated PS had larger impacts at higher quantiles of depressive symptoms. Quantile regression coefficients at the 75th percentile were at least 40% larger than at the 25th percentile in all three polygenic scoring algorithms. The interquartile range comparison suggested the effects of PS significantly differed at the 25th and 75th percentiles of the long-term depressive phenotype for the PGC-MDD-PS (P = 0.03), and this difference also reached borderline statistical significance for the GAIN-MDD-PS (P = 0.05).
Conclusions
Integrating multiple phenotype assessments spanning 14 years and applying different polygenic scoring approaches did not substantially improve genetic prediction of depression. Quantile regressions suggested the effects of PS may be largest at high quantiles of depressive symptom scores, presumably among people with additional, unobserved sources of vulnerability to depression.
doi:10.1002/brb3.205
PMCID: PMC3967544
Depression; GWAS; long-term cumulative phenotype; polygenic score; quantile regression
19.  First use of 18F-labeled ML-10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy 
Brain and Behavior  2014;4(2):312-315.
Objectives
The authors present the first use of the novel positron emission tomography (PET) apoptosis tracer 18F-labeled 2-(5-fluoro-pentyl)-2-methyl-malonic acid (18F-ML-10) for early-therapy response assessment of a newly diagnosed glioblastoma multiforme (GBM) patient.
Case report
A 71-year-old male with a newly diagnosed GBM received 18F-ML-10 PET scans prior to therapy initiation (baseline) and after completing 3 weeks of whole-brain radiation therapy with concomitant temozolomide chemotherapy (early-therapy assessment, ETA). The baseline 18F-ML-10 PET scan showed increased tracer uptake at the site of the GBM, with highest activity toward the central portion of the tumor. At the ETA time point, a new distribution of tracer uptake was observed compared to baseline. Normalized pixel-by-pixel subtraction of baseline from ETA was used to quantify change in tracer distribution between 18F-ML-10 PET imaging time points. Results of this analysis showed reduction in 18F-ML-10 uptake at the site of greatest baseline uptake, but increased uptake around the periphery of the tumor at the early-therapy time point.
Conclusion
The changing patterns of 18F-ML-10 uptake between baseline and ETA are suggestive for therapy-induced tumor cellular apoptosis.
doi:10.1002/brb3.217
PMCID: PMC3967545
18F-ML-10; early-therapy response assessment; glioblastoma multiforme; positron emission tomography
20.  Brain and Behavior: we want you to share your data 
Brain and Behavior  2013;4(1):1-3.
We at Brain and Behavior are happy, for one, that data sharing is now here.
doi:10.1002/brb3.192
PMCID: PMC3937699  PMID: 24653948
21.  Juvenile stress enhances anxiety and alters corticosteroid receptor expression in adulthood 
Brain and Behavior  2013;4(1):4-13.
Background
Exposure to stress in early life is correlated with the development of anxiety disorders in adulthood. The underlying mechanisms are not fully understood, but an imbalance in corticosteroid receptor (CR) expression in the limbic system, particularly the hippocampus, has been implicated in the etiology of anxiety disorders. However, little is known about how prepubertal stress in the so called “juvenile” period might alter the expression of these receptors.
Aims
Therefore, the aim of this study was to investigate how stress experienced in the juvenile phase of life altered hippocampal expression of CRs and anxiety behaviors in adulthood.
Materials and methods
We used a rodent model to assess the effects of juvenile stress on hippocampal CR expression, and performance in three behavioral tests of anxiety in adulthood.
Results
Juvenile stress (JS) increased anxiety-like behavior on the elevated plus maze, increased mineralocorticoid receptor (MR) expression, and decreased the ratio of glucocorticoid receptor (GR) to MR expression in the hippocampus of adult animals. Females demonstrated lower levels of anxiety-type behavior and increased activity in three behavioral tests, and had greater expression of GR and GR:MR ratio than males, regardless of treatment.
Discussion and conclusion
These results demonstrate that JS can alter the expression and balance of CRs, providing a potential mechanism for the corresponding increase in anxiety behavior observed in adulthood. Further evidence for the role of CR expression in anxiety is provided by sex differences in anxiety behavior and corresponding alterations in CR expression.
doi:10.1002/brb3.182
PMCID: PMC3937700  PMID: 24653949
Anxiety; glucocorticoid receptor; juvenile stress; mineralocorticoid receptor; sex differences
22.  Issue Information 
Brain and Behavior  2014;4(1):i-ii.
doi:10.1002/brb3.164
PMCID: PMC3937701  PMID: 24653960
23.  Amount and intensity of daily living activities in Charcot–Marie–Tooth 1A patients 
Brain and Behavior  2013;4(1):14-20.
Background
Charcot–Marie–Tooth 1A (CMT1A) patients show a reduction of spontaneous activities of daily living measured by means of questionnaires or pedometers, which are quite inaccurate compared to recent measurement techniques.
Aim
The study aimed at quantifying daily living activities in CMT1A patients by means of inertial sensors, which give information not only on the amount but also on the intensity of these activities.
Materials and methods
Time and count (amount), and velocity and power (intensity) of 24 h daily living activities were measured in eight patients (20–48 years; Barthel >90; Tinetti >20) and eight healthy individuals, matched for age and gender, by means of a wearable inertial sensor device.
Results
There were no differences between patients and controls in the 24-h distance covered and count of steps. However, count of step climbing and sit to stand were lower in patients than in controls (139.93 ± 141.66 vs. 341.06 ± 164.07 n and 58.23 ± 7.82 vs. 65.81 ± 4.75 n, respectively; P < 0.05) as well as mean daily step-climbing and walking velocities (1.07 ± 0.17 vs. 1.21 ± 0.10 m/sec and 1.16 ± 0.31 vs. 1.87 ± 0.50 m/sec, respectively; P < 0.05). In CMT1A patients there was a positive correlation between strength of the knee extensor muscles and both count of steps climbed (R = 0.80) and sit to stand (R = 0.79).
Discussion and conclusion
The reduced ability of CMT1A patients to carry out activities at high intensity, which was correlated with strength, suggests that strength training might be a rehabilitation tool for improving the 1 ability to carry out these activities.
doi:10.1002/brb3.187
PMCID: PMC3937702  PMID: 24653950
Energy expenditure; hereditary neuromuscular disorder; neuropathies; rehabilitation; speed of walking
24.  Age-related differences in auditory evoked potentials as a function of task modulation during speech–nonspeech processing 
Brain and Behavior  2013;4(1):21-28.
Background
Healthy aging is typically associated with impairment in various cognitive abilities such as memory, selective attention or executive functions. Less well observed is the fact that also language functions in general and speech processing in particular seems to be affected by age. This impairment is partly caused by pathologies of the peripheral auditory nervous system and central auditory decline and in some part also by a cognitive decay.
Aims
This cross-sectional electroencephalography (EEG) study investigates temporally early electrophysiological correlates of auditory related selective attention in young (20–32 years) and older (60–74 years) healthy adults.
Material and methods
In two independent tasks, we systematically modulate the subjects' focus of attention by presenting words and pseudowords as targets and white noise stimuli as distractors.
Results
Behavioral data showed no difference in task accuracy between the two age samples irrespective of the modulation of attention. However, our work is the first to show that the N1-and the P2 component evoked by speech and nonspeech stimuli are specifically modulated in older adults and young adults depending on the subjects' focus of attention.
Conclusion
This finding is particularly interesting in that the age-related differences in AEPs may be reflecting levels of processing that are not mirrored by the behavioral measurements.
doi:10.1002/brb3.188
PMCID: PMC3937703  PMID: 24653951
Aging; attention; EEG; N1; P2; speech
25.  Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease 
Brain and Behavior  2013;4(1):29-40.
Introduction
The brain mechanisms of cognitive impairment in prodromal Huntington disease (prHD) are not well understood. Although striatal atrophy correlates with some cognitive abilities, few studies of prHD have investigated whether cortical gray matter morphometry correlates in a regionally specific manner with functioning in different cognitive domains. This knowledge would inform the selection of cognitive measures for clinical trials that would be most sensitive to the target of a treatment intervention.
Method
In this study, random forest analysis was used to identify neuroanatomical correlates of functioning in five cognitive domains including attention and information processing speed, working memory, verbal learning and memory, negative emotion recognition, and temporal processing. Participants included 325 prHD individuals with varying levels of disease progression and 119 gene-negative controls with a family history of HD. In intermediate analyses, we identified brain regions that showed significant differences between the prHD and the control groups in cortical thickness and striatal volume. Brain morphometry in these regions was then correlated with cognitive functioning in each of the domains in the prHD group using random forest methods. We hypothesized that different regional patterns of brain morphometry would be associated with performances in distinct cognitive domains.
Results
The results showed that performances in different cognitive domains that are vulnerable to decline in prHD were correlated with regionally specific patterns of cortical and striatal morphometry. Putamen and/or caudate volumes were top-ranked correlates of performance across all cognitive domains, as was cortical thickness in regions related to the processing demands of each domain.
Conclusions
The results underscore the importance of identifying structural magnetic resonance imaging (sMRI) markers of functioning in different cognitive domains, as their relative sensitivity depends on the extent to which processing is called upon by different brain networks. The findings have implications for identifying neuroimaging and cognitive outcome measures for use in clinical trials.
doi:10.1002/brb3.185
PMCID: PMC3937704  PMID: 24653952
Cognition; magnetic resonance imaging; prodromal Huntington disease

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